Autoimmune diseases are debilitating disorders with wide ranges of causes and effects. Little is known about predisposing factors. A study of the mechanisms involved in an autoimmune response in humans is difficult to accomplish because of the multitude of variables and ramifications. However, the mouse strain, motheaten viable (mev), offers an excellent system in which to study autoimmunity at a molecular level. In these mice, the genetic cause for disease is known - a single mutation in a gene encoding a protein tyrosine phosphatase of hematopoietic cells, PTP1C. Phosphatases play critical roles in mediating signal transduction through a cell - from the most surface proximal signals to distal activation of transcription factors that regulate gene expression. I have discovered that the transcription factor, NFkB, is aberrantly expressed in mev immune cells; the transactivating subunit of NFkB, p65, is not found - only p50 and crel are detected. The cytoplasmic inhibitor of NFkB, IkB, is also not detectable in mev immune cells. These findings are novel and have not been previously described. To more closely examine the mechanisms responsible for the aberrant expression of these proteins, northern blots will be performed to determine whether mRNAs for these proteins are transcribed. In further steps, the degradation rates of NFkB/IkB proteins and nascent mRNA production in the nucleus will be evaluated. To correlate the role of PTP1C with the expression of aberrant NFkB/IkB proteins, transcription of PTP1C will be blocked or reduced, using antisense technology, in B cells which normally express NFkB/lkB, and the resulting effects on NFkB/IkB regulation assayed. To examine the effects of the mutant PTP1C in mev cells and define the signal transduction pathways, these cells will be activated with a number of stimuli, that transduce signals via different modes, and the effects on NFkB/IkB expression evaluated. Long term objectives are to define a model for induction of NFkB in autoimmune B cells and use this to target potential therapies such as employing antisense technology to reduce the expression of NFkB and alleviate the inflammatory response.